Honors & Awards
Propel Postdoctoral Scholar, Stanford University (2022-current)
Ruth L. Kirschstein NRSA for Individual Predoctoral Fellows (F31) Award, National Cancer Institute (2020-2021)
Graduate Research Fellowship Program, National Science Foundation (2017-2020)
Amgen Scholar, Amgen Foundation (2011)
Meyerhoff Scholars Program, University of Maryland, Baltimore County (2009-2013)
BS, University of Maryland, Baltimore County, Biological Sciences and Music (2013)
PhD, University of California, San Francisco, Biomedical Sciences (2021)
Michael Bassik, Postdoctoral Faculty Sponsor
Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer.
2022; 12 (9): 2198-2219
The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS-MAPK inhibition.SIGNIFICANCE: Reduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy-lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS-MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007.
View details for DOI 10.1158/2159-8290.CD-22-0044
View details for PubMedID 35771494
Selective autophagy of MHC-I promotes immune evasion of pancreatic cancer
2020; 16 (8): 1524-1525
Major histocompatibility complex class I (MHC-I) is a key molecule in anti-tumor adaptive immunity. MHC-I is essential for endogenous antigen presentation by cancer cells and subsequent recognition and clearance by CD8+ T cells. Defects in MHC-I expression occur frequently in several cancers, leading to impaired antigen presentation, immune evasion and/or resistance to immune checkpoint blockade (ICB) therapy. Pancreatic ductal adenocarcinoma (PDAC), a deadly malignancy with dismal patient prognosis, is resistant to ICB and shows frequent downregulation of MHC-I independent of genetic mutations abrogating MHC-I expression. Previously, we showed that PDAC cells exhibit elevated levels of autophagy and lysosomal biogenesis, which together support the survival and growth of PDAC tumors via both cell-autonomous and non-cell-autonomous mechanisms. In our recent study, we have identified NBR1-mediated selective macroautophagy/autophagy of MHC-I as a novel mechanism that facilitates immune evasion by PDAC cells. Importantly, autophagy or lysosome inhibition restores MHC-I expression, leading to enhanced anti-tumor T cell immunity and improved response to ICB in transplanted tumor models in syngeneic host mice. Our results highlight a previously unknown function of autophagy and the lysosome in regulation of immunogenicity in PDAC, and provide a novel therapeutic strategy for targeting this deadly disease.
View details for DOI 10.1080/15548627.2020.1769973
View details for Web of Science ID 000540843700001
View details for PubMedID 32459143
View details for PubMedCentralID PMC7469632
Systemic dysfunction and plasticity of the immune macroenvironment in cancer models
2020; 26 (7): 1125-+
Understanding of the factors governing immune responses in cancer remains incomplete, limiting patient benefit. In this study, we used mass cytometry to define the systemic immune landscape in response to tumor development across five tissues in eight mouse tumor models. Systemic immunity was dramatically altered across models and time, with consistent findings in the peripheral blood of patients with breast cancer. Changes in peripheral tissues differed from those in the tumor microenvironment. Mice with tumor-experienced immune systems mounted dampened responses to orthogonal challenges, including reduced T cell activation during viral or bacterial infection. Antigen-presenting cells (APCs) mounted weaker responses in this context, whereas promoting APC activation rescued T cell activity. Systemic immune changes were reversed with surgical tumor resection, and many were prevented by interleukin-1 or granulocyte colony-stimulating factor blockade, revealing remarkable plasticity in the systemic immune state. These results demonstrate that tumor development dynamically reshapes the composition and function of the immune macroenvironment.
View details for DOI 10.1038/s41591-020-0892-6
View details for Web of Science ID 000535417400001
View details for PubMedID 32451499
View details for PubMedCentralID PMC7384250
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I
2020; 581 (7806): 100-+
Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.
View details for DOI 10.1038/s41586-020-2229-5
View details for Web of Science ID 000528161900005
View details for PubMedID 32376951
View details for PubMedCentralID PMC7296553
Host Control of Tumor Feeding: Autophagy Holds the Key
2019; 29 (2): 236-238
Cancer cells are dependent on functional autophagy both within their cytoplasm and systemically in the host to maintain growth. How systemic autophagy directly contributes to tumor growth remains unclear. In a study published in Nature, Poillet-Perez et al. (2018) show that host autophagy helps to maintain the levels of circulating arginine that feed tumor growth.
View details for DOI 10.1016/j.cmet.2019.01.009
View details for Web of Science ID 000457708100003
View details for PubMedID 30726755