Debadrita Bhattacharya

All Publications

• Small cell lung cancer plasticity enables NFIB-independent metastasis. Cancer research Ko, J. H., Lambert, K. E., Bhattacharya, D., Lee, M. C., Colon, C. I., Hauser, H., Sage, J. 2023

  Abstract

  Metastasis is a major cause of morbidity and mortality in patients with cancer, highlighting the need to identify improved treatment and prevention strategies. Previous observations in pre-clinical models and tumors from patients with small cell lung cancer (SCLC), a fatal form of lung cancer with high metastatic potential, identified the transcription factor NFIB as a driver of tumor growth and metastasis. However, investigation into the requirement for NFIB activity for tumor growth and metastasis in relevant in vivo models is needed to establish NFIB as a therapeutic target. Here, using conditional gene knockout strategies in genetically engineered mouse models of SCLC, we found that upregulation of NFIB contributes to tumor progression, but NFIB is not required for metastasis. Molecular studies in NFIB wild-type and knockout tumors identified the pioneer transcription factors FOXA1/2 as candidate drivers of metastatic progression. Thus, while NFIB upregulation is a frequent event in SCLC during tumor progression, SCLC tumors can employ NFIB-independent mechanisms for metastasis, further highlighting the plasticity of these tumors.

  View details for DOI 10.1158/0008-5472.CAN-23-1079

  View details for PubMedID 37963187

• Crosstalk between small-cell lung cancer cells and astrocytes mimics brain development to promote brain metastasis. Nature cell biology Qu, F., Brough, S. C., Michno, W., Madubata, C. J., Hartmann, G. G., Puno, A., Drainas, A. P., Bhattacharya, D., Tomasich, E., Lee, M. C., Yang, D., Kim, J., Peiris-Pagès, M., Simpson, K. L., Dive, C., Preusser, M., Toland, A., Kong, C., Das, M., Winslow, M. M., Pasca, A. M., Sage, J. 2023

  Abstract

  Brain metastases represent an important clinical problem for patients with small-cell lung cancer (SCLC). However, the mechanisms underlying SCLC growth in the brain remain poorly understood. Here, using intracranial injections in mice and assembloids between SCLC aggregates and human cortical organoids in culture, we found that SCLC cells recruit reactive astrocytes to the tumour microenvironment. This crosstalk between SCLC cells and astrocytes drives the induction of gene expression programmes that are similar to those found during early brain development in neurons and astrocytes. Mechanistically, the brain development factor Reelin, secreted by SCLC cells, recruits astrocytes to brain metastases. These astrocytes in turn promote SCLC growth by secreting neuronal pro-survival factors such as SERPINE1. Thus, SCLC brain metastases grow by co-opting mechanisms involved in reciprocal neuron-astrocyte interactions during brain development. Targeting such developmental programmes activated in this cancer ecosystem may help prevent and treat brain metastases.

  View details for DOI 10.1038/s41556-023-01241-6

  View details for PubMedID 37783795

  View details for PubMedCentralID 6602095

• Radiotherapy in combination with CD47 blockade elicits a macrophage-mediated abscopal effect. Nature cancer Nishiga, Y., Drainas, A. P., Baron, M., Bhattacharya, D., Barkal, A. A., Ahrari, Y., Mancusi, R., Ross, J. B., Takahashi, N., Thomas, A., Diehn, M., Weissman, I. L., Graves, E. E., Sage, J. 2022

  Abstract

  Radiation therapy is a mainstay of cancer treatment but does not always lead to complete tumor regression. Here we combine radiotherapy with blockade of the 'don't-eat-me' cell-surface molecule CD47 in small cell lung cancer (SCLC), a highly metastatic form of lung cancer. CD47 blockade potently enhances the local antitumor effects of radiotherapy in preclinical models of SCLC. Notably, CD47 blockade also stimulates off-target 'abscopal' effects inhibiting non-irradiated SCLC tumors in mice receiving radiation. These abscopal effects are independent of T cells but require macrophages that migrate into non-irradiated tumor sites in response to inflammatory signals produced by radiation and are locally activated by CD47 blockade to phagocytose cancer cells. Similar abscopal antitumor effects were observed in other cancer models treated with radiation and CD47 blockade. The systemic activation of antitumor macrophages following radiotherapy and CD47 blockade may be particularly important in patients with cancer who suffer from metastatic disease.

  View details for DOI 10.1038/s43018-022-00456-0

  View details for PubMedID 36411318

• Spatial epitope barcoding reveals clonal tumor patch behaviors. Cancer cell Rovira-Clave, X., Drainas, A. P., Jiang, S., Bai, Y., Baron, M., Zhu, B., Dallas, A. E., Lee, M. C., Chu, T. P., Holzem, A., Ayyagari, R., Bhattacharya, D., McCaffrey, E. F., Greenwald, N. F., Markovic, M., Coles, G. L., Angelo, M., Bassik, M. C., Sage, J., Nolan, G. P. 2022

  Abstract

  Intratumoral heterogeneity is a seminal feature of human tumors contributing to tumor progression and response to treatment. Current technologies are still largely unsuitable to accurately track phenotypes and clonal evolution within tumors, especially in response to genetic manipulations. Here, we developed epitopes for imaging using combinatorial tagging (EpicTags), which we coupled to multiplexed ion beam imaging (EpicMIBI) for in situ tracking of barcodes within tissue microenvironments. Using EpicMIBI, we dissected the spatial component of cell lineages and phenotypes in xenograft models of small cell lung cancer. We observed emergent properties from mixed clones leading to the preferential expansion of clonal patches for both neuroendocrine and non-neuroendocrine cancer cell states in these models. In a tumor model harboring a fraction of PTEN-deficient cancer cells, we observed a non-autonomous increase of clonal patch size in PTEN wild-type cancer cells. EpicMIBI facilitates in situ interrogation of cell-intrinsic and cell-extrinsic processes involved in intratumoral heterogeneity.

  View details for DOI 10.1016/j.ccell.2022.09.014

  View details for PubMedID 36240778

• Pluripotency factors are repurposed to shape the epigenomic landscape of neural crest cells. Developmental cell Hovland, A. S., Bhattacharya, D., Azambuja, A. P., Pramio, D., Copeland, J., Rothstein, M., Simoes-Costa, M. 2022; 57 (19): 2257-2272.e5

  Abstract

  Yamanaka factors are essential for establishing pluripotency in embryonic stem cells, but their function in multipotent stem cell populations is poorly understood. Here, we show that OCT4 and SOX2 cooperate with tissue-specific transcription factors to promote neural crest formation. By assessing avian and human neural crest cells at distinct developmental stages, we characterized the epigenomic changes that occur during their specification, migration, and early differentiation. This analysis determined that the OCT4-SOX2 dimer is required to establish a neural crest epigenomic signature that is lost upon cell fate commitment. The OCT4-SOX2 genomic targets in the neural crest differ from those of embryonic stem cells, indicating the dimer displays context-specific functions. Binding of OCT4-SOX2 to neural crest enhancers requires pioneer factor TFAP2A, which physically interacts with the dimer to modify its genomic targets. Our results demonstrate how Yamanaka factors are repurposed in multipotent cells to control chromatin organization and define their developmental potential.

  View details for DOI 10.1016/j.devcel.2022.09.006

  View details for PubMedID 36182685

• Neural crest metabolism: At the crossroads of development and disease DEVELOPMENTAL BIOLOGY Bhattacharya, D., Khan, B., Simoes-Costa, M. 2021; 475: 245-255

  Abstract

  The neural crest is a migratory stem cell population that contributes to various tissues and organs during vertebrate embryonic development. These cells possess remarkable developmental plasticity and give rise to many different cell types, including chondrocytes, osteocytes, peripheral neurons, glia, melanocytes, and smooth muscle cells. Although the genetic mechanisms underlying neural crest development have been extensively studied, many facets of this process remain unexplored. One key aspect of cellular physiology that has gained prominence in the context of embryonic development is metabolic regulation. Recent discoveries in neural crest biology suggest that metabolic regulation may play a central role in the formation, migration, and differentiation of these cells. This possibility is further supported by clinical studies that have demonstrated a high prevalence of neural crest anomalies in babies with congenital metabolic disorders. Here, we examine why neural crest development is prone to metabolic disruption and discuss how carbon metabolism regulates developmental processes like epithelial-to-mesenchymal transition (EMT) and cell migration. Finally, we explore how understanding neural crest metabolism may inform upon the etiology of several congenital birth defects.

  View details for DOI 10.1016/j.ydbio.2021.01.018

  View details for Web of Science ID 000651137900006

  View details for PubMedID 33548210

• Metabolic Reprogramming Promotes Neural Crest Migration via Yap/Tead Signaling DEVELOPMENTAL CELL Bhattacharya, D., Azambuja, A., Simoes-Costa, M. 2020; 53 (2): 199-+

  Abstract

  The Warburg effect is one of the metabolic hallmarks of cancer cells, characterized by enhanced glycolysis even under aerobic conditions. This physiological adaptation is associated with metastasis , but we still have a superficial understanding of how it affects cellular processes during embryonic development. Here we report that the neural crest, a migratory stem cell population in vertebrate embryos, undergoes an extensive metabolic remodeling to engage in aerobic glycolysis prior to delamination. This increase in glycolytic flux promotes Yap/Tead signaling, which activates the expression of a set of transcription factors to drive epithelial-to-mesenchymal transition. Our results demonstrate how shifts in carbon metabolism can trigger the gene regulatory circuits that control complex cell behaviors. These findings support the hypothesis that the Warburg effect is a precisely regulated developmental mechanism that is anomalously reactivated during tumorigenesis and metastasis.

  View details for DOI 10.1016/j.devcel.2020.03.005

  View details for Web of Science ID 000526953300009

  View details for PubMedID 32243782

  View details for PubMedCentralID PMC7236757

• Control of neural crest multipotency by Wnt signaling and the Lin28/let-7 axis ELIFE Bhattacharya, D., Rothstein, M., Azambuja, A., Simoes-Costa, M. 2018; 7

  Abstract

  A crucial step in cell differentiation is the silencing of developmental programs underlying multipotency. While much is known about how lineage-specific genes are activated to generate distinct cell types, the mechanisms driving suppression of stemness are far less understood. To address this, we examined the regulation of the transcriptional network that maintains progenitor identity in avian neural crest cells. Our results show that a regulatory circuit formed by Wnt, Lin28a and let-7 miRNAs controls the deployment and the subsequent silencing of the multipotency program in a position-dependent manner. Transition from multipotency to differentiation is determined by the topological relationship between the migratory cells and the dorsal neural tube, which acts as a Wnt-producing stem cell niche. Our findings highlight a mechanism that rapidly silences complex regulatory programs, and elucidate how transcriptional networks respond to positional information during cell differentiation.

  View details for DOI 10.7554/eLife.40556

  View details for Web of Science ID 000453819200001

  View details for PubMedID 30520734

  View details for PubMedCentralID PMC6301792

• The molecular basis of neural crest axial identity DEVELOPMENTAL BIOLOGY Rothstein, M., Bhattacharya, D., Simoes-Costa, M. 2018; 444: S170-S180

  Abstract

  The neural crest is a migratory cell population that contributes to multiple tissues and organs during vertebrate embryonic development. It is remarkable in its ability to differentiate into an array of different cell types, including melanocytes, cartilage, bone, smooth muscle, and peripheral nerves. Although neural crest cells are formed along the entire anterior-posterior axis of the developing embryo, they can be divided into distinct subpopulations based on their axial level of origin. These groups of cells, which include the cranial, vagal, trunk, and sacral neural crest, display varied migratory patterns and contribute to multiple derivatives. While these subpopulations have been shown to be mostly plastic and to differentiate according to environmental cues, differences in their intrinsic potentials have also been identified. For instance, the cranial neural crest is unique in its ability to give rise to cartilage and bone. Here, we examine the molecular features that underlie such developmental restrictions and discuss the hypothesis that distinct gene regulatory networks operate in these subpopulations. We also consider how reconstructing the phylogeny of the trunk and cranial neural crest cells impacts our understanding of vertebrate evolution.

  View details for DOI 10.1016/j.ydbio.2018.07.026

  View details for Web of Science ID 000464483000014

  View details for PubMedID 30071217

  View details for PubMedCentralID PMC6355384