Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation
Meri Rogava1,2,3, Tyler J Aprati4, Wei-Yu Chi5,6,7
1Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Abstract:
Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.
Insights
Loss of Pip4k2c promotes liver metastasis by exploiting insulin signaling. This mechanism, distinct from lung metastasis, offers new therapeutic targets like SGLT2 inhibitors or ketogenic diets to combat liver-specific cancer spread.
Area of Science:
- Oncology
- Metabolic Signaling
- Cancer Metastasis
Background:
- Liver metastasis (LM) is a major cause of cancer mortality, associated with poor survival and treatment resistance.
- The specific mechanisms driving organotropism to the liver remain largely unknown.
- Understanding liver-metastatic organotropism is crucial for developing targeted therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying liver-specific metastasis.
- To identify genetic factors and signaling pathways that confer organotropism to the liver.
- To explore potential therapeutic strategies targeting liver metastasis.
Main Methods:
- In vivo CRISPR-Cas9 screening to identify genes regulating liver metastasis.
- Analysis of Pip4k2c-deficient cancer cell behavior in response to insulin signaling.
- Examination of PIP4K2C expression and metabolic changes in patient melanoma samples.
- In vivo studies evaluating PI3K inhibition, SGLT2 inhibitors, and ketogenic diets in mouse models.
Main Results:
- Loss of Pip4k2c specifically promoted liver metastasis, without affecting lung metastasis or primary tumor growth.
- Pip4k2c-deficient cells exhibited hypersensitivity to insulin-mediated PI3K/AKT signaling, utilizing the liver's insulin-rich environment.
- Concordant changes in PIP4K2C expression and distinct metabolic profiles were observed in patient melanomas.
- Systemic PI3K inhibition worsened LM, but this was counteracted by SGLT2 inhibitors or ketogenic diets.
Conclusions:
- Pip4k2c loss drives liver organotropism by co-opting insulin signaling within the hepatic microenvironment.
- This study reveals a novel mechanism of metastatic organotropism exploiting physiological metabolic cues.
- Targeting insulin signaling pathways or metabolic interventions like ketogenic diets shows promise for treating liver metastasis.
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:20The JAK-STAT Signaling Pathway
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...