The role of Collagen XVII and the hemidesmosome in stroma-driven progression and invasiveness of pancreatic cancer
Final Report Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal malignancies characterized by a highly desmoplastic stroma, primarily composed of an abundant fibrosis and cancerassociated fibroblasts. Desmoplasia and PDAC tumor cells are part of a complex interaction network determining the course of PDAC tumor progression and cancer cell dissemination. The basic science projects at the host institution (Pancreatic Research Laboratory, Massachusetts General Hospital, Harvard Medical School) were dedicated to investigating cancer cell-stroma cross-talk. The hemidesmosome component collagen XVII was identified as a key player for interaction between PDAC cancer cells and fibroblasts in vitro and in vivo. We found collagen XVII expression exclusively in the epithelial compartment of PDAC, and increasing expression levels correlated with worse outcomes. Collagen XVII expression was induced by fibroblasts. A loss of collagen XVII led to reduced cell viability and migratory potential. In vivo experiments confirmed decreased tumor proliferation in collagen XVII knockout mice. We further demonstrated that the effects of collagen XVII were mediated via the PI3K/AKT pathway and PIK3R5. A thorough transcriptomic analysis of PDAC stroma in patient-derived xenograft models disclosed tumor and stroma heterogeneity. Four different stromal subtypes were identified based on related major pathways: An immunogenic subtype, an EMT-driven subtype, an invasion-driven subtype and a quiescent subtype. Drug screening studies showed differential treatment response to potential stroma-targeted agents among the subtypes. Further drug screening for sonic hedgehog (SHH) neutralizing antibodies in patient-derived xenograft models showed that inhibition of SHH affected tumor growth, stromal content, and vascularity. Its effect on the Hh signaling pathway was restricted to the stromal compartment. SHH-stimulated angiogenesis indirectly through the reduction of antiangiogenic THBS2 and TIMP2 in stromal cells. An additional direct effect of SHH on endothelial cells depended on the presence of VEGF. In an additional clinical project, we defined simplified radiological criteria to predict resectability in upfront resected PDAC patients as compared to those with neoadjuvant therapy. These criteria were more accurate in predicting margin status than current gold-standard criteria. In a multicenter clinical study of small non-functional pancreatic neuroendocrine tumors (pNET), we investigated short- and long-term outcomes of parenchyma- and lymph node-sparing procedures. While short-term outcomes were in favor of parenchyma- and lymph node-sparing procedures, long-term outcomes were equivalent to oncological resections.
Publications
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Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer. Angiogenesis. 2020 Aug;23(3):479-492
Bausch D, Fritz S, Bolm L, Wellner UF, Fernandez-Del-Castillo C, Warshaw AL, Thayer SP, Liss AS
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Long Term Outcomes of Parenchyma-Sparing and Oncologic Resections in Patients with Non-Functional Pancreatic Neuroendocrine Tumors <3cm in a Large Multi-Center Cohort. Ann Surg. 2022
Bolm L, Nebbia M, Wei AC, Zureikat AH, Fernández-Del Castillo C, Zheng J, Pulvirenti A, Javed AA, Sekigami Y, Petruch N, Qadan M, Lillemoe KD, He J, Ferrone CR; PAncreatic Neuroendocrine Disease Alliance (PANDA)
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Prediction of R Status in Resections for Pancreatic Cancer Using Simplified Radiological Criteria. Ann Surg. 2022
Bolm L, Pisuchpen N, Qadan M, Kambadakone A, Sondermann S, Mueller K, Petruch N, May K, Zelga P, Nebbia M, Michelakos T, Baba T, Roldan J, Harrison JM, Honselmann KC, Keck T, Lillemoe KD, Ferrone CR, Wellner UF, Fernandez-del Castillo C
