Joseph Mancias

The Mancias Lab, located at the Dana-Farber Cancer Institute is focused on the study of pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the most vexing problems in cancer with 5-year overall survival rates of 13%, thus there is a strong need for new therapeutic targets. Our ongoing work seeks to define the role of autophagy and iron metabolism in PDAC and identify novel therapeutic targets in PDAC. To accomplish our aims, our laboratory leverages deep scientific expertise in pancreatic cancer biology and our technical expertise in mass spectrometry-based quantitative proteomics, cell biology, and patient-derived and mouse models of PDAC.

PDAC have a distinct dependence on autophagy, a conserved catabolic pathway that targets proteins and damaged organelles for lysosomal degradation to maintain cell metabolism, genomic integrity, and cell survival. The unique importance of autophagy in PDAC suggests that there may be a subset of proteins that are specifically targeted by autophagy for degradation, which would promote proliferation and survival, and that these may represent new targets for therapy. Using a quantitative pancreatic cancer autophagosomal proteomics approach, we identified NCOA4 as the autophagy receptor for ferritin autophagy and degradation (ferritinophagy). We further identified, using cellular and mouse models, that ferritinophagy is a highly regulated process and plays a central role in the larger context of cellular and organismal iron homeostasis. Given the reliance of PDAC on both high levels of autophagy as well as iron, we subsequently studied the role of NCOA4 and ferritinophagy in PDAC thereby identifying NCOA4-mediated ferritinophagy as a PDAC dependency and therapeutic target critical for maintenance of PDAC iron homeostasis. Furthermore, in collaboration, we have determined that NCOA4-mediated ferritinophagy is further upregulated in PDAC in response to KRAS/MAPK pathway inhibition thereby nominating KRAS and ferritinophagy inhibition as a promising combination therapy to circumvent resistance to KRAS inhibition. Most recently, we have determined the cryo-EM structure of the NCOA4-ferritin complex. This structure is facilitating ongoing work to discover inhibitors of this interaction for evaluation in pre-clinical PDAC models. Another major question in the PDAC autophagy field is the role of autophagy during PDAC tumor evolution and metastasis. Progress in this area has been hampered by the lack of proteomic tools to comprehensively evaluate the autophagosome/lysosome proteome in vivo. We have now developed a next-generation, in vivo capable lysosomal proteomics technique and profiled lysosomal proteomes from primary PDAC tumor, lung and liver metastases. Our work highlights shared and unique features in the lysosomal proteome of tumor cells growing in different tissues. We have now identified PDAC site-specific (primary pancreatic tumor versus lung metastasis versus liver metastasis) functional dependencies where, for instance, inhibition of an autophagic pathway affects liver metastases but not primary pancreatic tumor growth. This work promises to revolutionize our understanding of the role of autophagy in PDAC during tumor evolution and metastasis and uncover additional strategies for targeted autophagy inhibition.

The second major area of research focus in the laboratory is identifying and targeting therapeutic resistance in PDAC. An ongoing challenge for pancreatic cancer patients is the lack of effective targeted therapies and the development of therapeutic resistance to almost all therapies used for PDAC patients. We developed an integrated quantitative temporal proteomics, metabolomics and in vitro and in vivo drug-anchored genetic loss-of-function screening platform for discovery of therapeutic resistance in PDAC. We used this platform to identify mechanisms of resistance to promising newly developed targeted therapies including recently developed KRAS and RAS inhibitors being evaluated in clinical trials in PDAC currently.  In synergy with our other major area of research on the role of autophagy in PDAC, we and others have identified that upregulation of autophagy, and particularly ferritinophagy, is a major mechanism of resistance to KRAS inhibition in PDAC. This work has laid the groundwork for future clinical translation of combination therapy strategies in PDAC and ongoing efforts in the laboratory to identify inhibitors of ferritinophagy.