Joshua Rico

All Publications

• Forward genetic screening in engineered colorectal cancer organoids identifies regulators of metastasis. Proceedings of the National Academy of Sciences of the United States of America Wang, X., Cramer, Z., Leu, N. A., Monaghan, K., Durning, K., Adams-Tzivelekidis, S., Rhoades, J. H., Heintz, J., Tian, Y., Rico, J., Mendez, D., Petroni, R., King, A. C., Kim, M. S., Matsuda, R., Hanselman, O., Shin, A. E., Carrera Rodríguez, M. F., Brodsky, I. E., Rustgi, A., Li, N., Lengner, C. J., Andrés Blanco, M. 2025; 122 (46): e2510910122

  Abstract

  Metastatic outgrowth requires that cancer cells delaminate from the primary tumor, intravasate, survive in circulation, extravasate, migrate to, and proliferate at a distal site. Recurrent genetic drivers of metastasis remain elusive, suggesting that unlike the early steps of oncogenesis, metastasis drivers may be variable. We develop a framework for identifying metastasis regulators using CRISPR/Cas9-based screening in a genetically defined organoid model of colorectal adenocarcinoma. We conduct in vitro screens for invasion and migration alongside orthotopic, in vivo screens for gain of metastasis in a syngeneic mouse model. We identify CTNNA1 and BCL2L13 as bona fide metastasis-specific suppressors which do not confer any selective advantage in primary tumors. CTNNA1 loss promotes cell invasion and migration, and BCL2L13 loss promotes anchorage-independent survival and non-cell-autonomous changes to macrophage polarization. This study demonstrates proof of principle that large-scale genetic screening can be performed in tumor-organoid models in vivo and identifies novel regulators of metastasis.

  View details for DOI 10.1073/pnas.2510910122

  View details for PubMedID 41218116

• Editing stem cell genomes at scale to measure variant effects in diverse cell and genetic contexts. medRxiv : the preprint server for health sciences Fayer, S., Garge, R. K., Hopkins, M., Friedman, C. E., McGee, A. V., Rico, J., Powell, R. L., McDermot, E., Smith, N. T., Pendyala, S., Richardson, M. E., Smith, E. D., Bowen, B. M., Resnick, R., Gupta, P., Stergachis, A. B., Gifford, C., Pinglay, S., Yang, K. C., Fowler, D. M., Starita, L. M. 2025

  Abstract

  Multiplexed assays of variant effect (MAVEs) systematically measure variant function but have been limited to cancer cell lines rather than disease-relevant cell types. We developed saturation genome editing in human iPSCs (iPSC-SGE) to introduce variant libraries into a single allele of a target gene while programming the genetic background of the second allele, enabling variant assessment across differentiated cell types and genetic contexts at scale. We edited 1,137 variants into MYBPC3 and measured protein abundance in cardiomyocytes and cardiac organoids, accurately identifying pathogenic variants, and resolving variants of uncertain significance. Highlighting the importance of genetic context, we edited 437 POLG variants in two genetic backgrounds and identified loss-of-function and dominant-negative variants. Finally, we illuminate a path for scaling iPSC-SGE by identifying 443 disease genes essential for iPSC or iPSC-derived neuron growth. iPSC-SGE enables systematic assessment of variants in specialized human cell types, advancing MAVEs to empower genomic medicine.

  View details for DOI 10.1101/2025.11.12.25340127

  View details for PubMedID 41292636

  View details for PubMedCentralID PMC12642741

• Combinatorial inhibition of LSD1 and Menin induces therapeutic differentiation in AML. bioRxiv : the preprint server for biology Rodríguez, M. F., Rico, J., Vijayaraghavan, M., Yan, F., King, A., Petroni, R., Leu, N. A., Goodrow, H., Bernt, K., McGeehan, G., Blanco, M. A. 2025

  Abstract

  Acute myeloid leukemia (AML) is characterized by differentiation arrest and uncontrolled proliferation. Differentiation therapy aims to treat AML by de-repressing latent myeloid maturation programs to induce cell cycle arrest and subsequent cell death. This approach is curative in the promyelocytic AML subtype, but has met with limited success in other subtypes. Genes such as LSD1 have emerged as intriguing non-APL AML differentiation therapy targets, but results as monoagents in clinical trials have been mixed. Here, we performed differentiation-specific CRISPR screens to identify targets whose inhibition synergizes with LSD1 inhibition to induce terminal differentiation of non-APL AML cells. Intriguingly, the MLL co-factor Menin scored as the top hit. Using cell lines, primary patient samples, and mouse AML models, we find that dual inhibition of LSD1 and Menin is a highly promising approach for differentiation therapy. Mechanistically, we determine that inhibition of Menin downregulates drivers of proliferation and stemness such as MEIS1, and inhibition of LSD1 induces inflammatory and interferon-related pro-myeloid differentiation expression programs. Surprisingly, we find that this combination is effective in selected AML models without mutations in MLL or NPM1, thus nominating dual inhibition of LSD1 and Menin as an attractive therapeutic approach for a mutationally diverse set of non-APL AMLs.

  View details for DOI 10.1101/2025.11.09.687496

  View details for PubMedID 41292878

  View details for PubMedCentralID PMC12642425

• Deep learning the dynamic regulatory sequence code of cardiac organoid differentiation. bioRxiv : the preprint server for biology Metzl-Raz, E., Zhao, R., Deshpande, S., Powell, J., Porter, E. G., Zouaghi, Y., Liu, B. B., Kim, S. H., Abdi, I., Evergreen, I., Agarwal, M., Sheth, M. U., Rico, J., Miyamoto, M., Sanchez, J. M., Engreitz, J. M., Kundaje, A., Greenleaf, W. J., Gifford, C. A. 2025

  Abstract

  Defining the temporal gene regulatory programs that drive human organogenesis is essential for understanding the origins of congenital disease. We combined a time-resolved, single-cell multi-omic atlas of human iPSC-derived cardiac organoids with deep learning models that predict chromatin accessibility from DNA sequence, enabling the discovery of the regulatory syntax underlying early heart development. This framework uncovered cell-state-specific rules of cardiogenesis, including context-dependent activities of TEAD, HAND, and TBX transcription factor families, and linked these motifs to their target genes. We identified distinct programs guiding lineage divergence, such as ventricular versus pacemaker cardiomyocytes, and validated predictions by perturbing Myocardin (MYOCD), establishing its essential role in ventricular specification. Integration of chromatin, transcriptional, and genetic data further highlighted regulatory regions and disease-associated variants that perturb differentiation state transitions, supporting evidence that suggests congenital heart disease emerges early in development. This work bridges developmental gene regulation with disease genetics, providing a foundation for mechanistic and therapeutic insights into congenital diseases.

  View details for DOI 10.1101/2025.10.15.680997

  View details for PubMedID 41279701

  View details for PubMedCentralID PMC12632746

• ΔNp63 regulates MDSC survival and metabolism in triple-negative breast cancer. iScience Kim, U., Debnath, R., Maiz, J. E., Rico, J., Sinha, S., Blanco, M. A., Chakrabarti, R. 2024; 27 (4): 109366

  Abstract

  Triple-negative breast cancer (TNBC) contributes greatly to mortality of breast cancer, demanding new targetable options. We have shown that TNBC patients have high ΔNp63 expression in tumors. However, the function of ΔNp63 in established TNBC is yet to be explored. In current studies, targeting ΔNp63 with inducible CRISPR knockout and Histone deacetylase inhibitor Quisinostat showed that ΔNp63 is important for tumor progression and metastasis in established tumors by promoting myeloid-derived suppressor cell (MDSC) survival through tumor necrosis factor alpha. Decreasing ΔNp63 levels are associated with decreased CD4+ and FOXP3+ T-cells but increased CD8+ T-cells. RNA sequencing analysis indicates that loss of ΔNp63 alters multiple MDSC properties such as lipid metabolism, chemotaxis, migration, and neutrophil degranulation besides survival. We further demonstrated that targeting ΔNp63 sensitizes chemotherapy. Overall, we showed that ΔNp63 reprograms the MDSC-mediated immunosuppressive functions in TNBC, highlighting the benefit of targeting ΔNp63 in chemotherapy-resistant TNBC.

  View details for DOI 10.1016/j.isci.2024.109366

  View details for PubMedID 38510127

  View details for PubMedCentralID PMC10951988

• KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs CANCER DISCOVERY Yan, F., Li, J., Milosevic, J., Petroni, R., Liu, S., Shi, Z., Yuan, S., Reynaga, J. M., Qi, Y., Rico, J., Yu, S., Liu, Y., Rokudai, S., Palmisiano, N., Meyer, S. E., Sung, P. J., Wan, L., Lan, F., Garcia, B. A., Stanger, B. Z., Sykes, D. B., Blanco, M. 2022; 12 (3): 792-811

  Abstract

  Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML.AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a "writer-reader" epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587.

  View details for Web of Science ID 000767244100001

  View details for PubMedID 34853079

  View details for PubMedCentralID PMC8916037

• Chromatin-state barriers enforce an irreversible mammalian cell fate decision CELL REPORTS Blanco, M., Sykes, D. B., Gu, L., Wu, M., Petroni, R., Karnik, R., Wawer, M., Rico, J., Li, H., Jacobus, W. D., Jambhekar, A., Cheloufi, S., Meissner, A., Hochedlinger, K., Scadden, D. T., Shi, Y. 2021; 37 (6): 109967

  Abstract

  Stem and progenitor cells have the capacity to balance self-renewal and differentiation. Hematopoietic myeloid progenitors replenish more than 25 billion terminally differentiated neutrophils every day under homeostatic conditions and can increase this output in response to stress or infection. At what point along the spectrum of maturation do progenitors lose capacity for self-renewal and become irreversibly committed to differentiation? Using a system of conditional myeloid development that can be toggled between self-renewal and differentiation, we interrogate determinants of this "point of no return" in differentiation commitment. Irreversible commitment is due primarily to loss of open regulatory site access and disruption of a positive feedback transcription factor activation loop. Restoration of the transcription factor feedback loop extends the window of cell plasticity and alters the point of no return. These findings demonstrate how the chromatin state enforces and perpetuates cell fate and identify potential avenues for manipulating cell identity.

  View details for DOI 10.1016/j.celrep.2021.109967

  View details for Web of Science ID 000718274400006

  View details for PubMedID 34758323

• Kinetic Model of Metabolism of Monoclonal Antibody Producing CHO Cells CURRENT METABOLOMICS Rico, J., Nantel, A., Phuong Lan Pham, Voyer, R., Durocher, Y., Penny, S., Surendra, A., Pinto, D., Sasseville, M., Culf, E., Leclerc, S., van het Hoog, M., Cuperlovic-Culf, M. 2018; 6 (3): 207-217

  View details for DOI 10.2174/2213235X06666180803112546

  View details for Web of Science ID 000456363800006