Final Report Summary - HALLMARKS-TO-THERAPY (Intersecting hallmarks of cancer: mechanisms of and interplay between invasion and angiogenesis, guiding new strategies for cancer therapy)
Two conceptually important achievements bear emphasis.
In the first, we report that the NMDAR adapter protein GKAP acts as a genetic modulator of NMDAR signaling to govern invasive tumor growth (Li, Zeng, Cancer Cell 2018). Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). We establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/ inhibited NMDAR activity significantly associate with favorable patient prognosis in several cancer types. Genetic linkage analyses have associated multiple cancer modifier loci with disease susceptibility, malignant phenotypes, and responses to treatment. However, functional validation of cancer modifier genes has been challenging and insights into the underlying mechanistic basis has been limited. In this proof-of-concept study, we used genetically engineered mouse models derived from distinct strain backgrounds to explore the validation process: we began with a candidate invasion modifier gene, Dlgap1 (which encodes GKAP protein), suggested by genetic linkage analysis, and went on to establish its role as a modifier of invasive growth orchestrated by NMDAR signaling. Using refined bioinformatics algorithms, we identified a signature for tumors lacking NMDAR-GKAP pathway activity that predicts better prognosis in various cancer types, suggestive of broader involvement of this pathway in malignancy. Unpublished work in progress extends its involvement to the metastasis of breast cancer cell to the brain.
In the second major achievement, we report a fascinating new form of the now well-accepted principle that tumors treated with potent inhibitors of angiogenesis develop forms or adaptive or evasive resistance that limits therapeutic efficacy. (Allen, et al Cell Reports, 2016). Therapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1a-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2. Thus pre-clinical trials co-targeting the hallmark capabilities of "re-programming energetics/metabolism (with the mTOR inhibitor rapamycin) and "angiogenesis" (with the VEGFR/PDGFR inhibitor sunitinib) increases survival over either monotherapy, encouraging translational consideration.
In the first, we report that the NMDAR adapter protein GKAP acts as a genetic modulator of NMDAR signaling to govern invasive tumor growth (Li, Zeng, Cancer Cell 2018). Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). We establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/ inhibited NMDAR activity significantly associate with favorable patient prognosis in several cancer types. Genetic linkage analyses have associated multiple cancer modifier loci with disease susceptibility, malignant phenotypes, and responses to treatment. However, functional validation of cancer modifier genes has been challenging and insights into the underlying mechanistic basis has been limited. In this proof-of-concept study, we used genetically engineered mouse models derived from distinct strain backgrounds to explore the validation process: we began with a candidate invasion modifier gene, Dlgap1 (which encodes GKAP protein), suggested by genetic linkage analysis, and went on to establish its role as a modifier of invasive growth orchestrated by NMDAR signaling. Using refined bioinformatics algorithms, we identified a signature for tumors lacking NMDAR-GKAP pathway activity that predicts better prognosis in various cancer types, suggestive of broader involvement of this pathway in malignancy. Unpublished work in progress extends its involvement to the metastasis of breast cancer cell to the brain.
In the second major achievement, we report a fascinating new form of the now well-accepted principle that tumors treated with potent inhibitors of angiogenesis develop forms or adaptive or evasive resistance that limits therapeutic efficacy. (Allen, et al Cell Reports, 2016). Therapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1a-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2. Thus pre-clinical trials co-targeting the hallmark capabilities of "re-programming energetics/metabolism (with the mTOR inhibitor rapamycin) and "angiogenesis" (with the VEGFR/PDGFR inhibitor sunitinib) increases survival over either monotherapy, encouraging translational consideration.