Non-cell-autonomous cancer progression from chromosomal instability

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Chromosomal instability (CIN) is a known driver of cancer metastasis.
• The role of the immune system in CIN-driven metastasis is not fully understood.

Purpose of the Study:

• To investigate how CIN-induced chronic activation of the cGAS-STING pathway influences the tumor microenvironment and metastasis.
• To explore therapeutic strategies targeting the cGAS-STING pathway in CIN-driven cancers.

Main Methods:

• Utilized ContactTracing, a novel tool for analyzing cell-cell interactions from single-cell transcriptomic data.
• Investigated CIN-induced signaling in cancer cells, including cGAS-STING pathway activation, interferon response, and endoplasmic reticulum (ER) stress.
• Assessed the impact of CIN reversal, STING depletion, and ER stress inhibition on metastasis in immune-competent and compromised models.
• Evaluated STING inhibitors in preclinical models of melanoma, breast, and colorectal cancers.
• Analyzed human triple-negative breast cancer (TNBC) for associations between CIN, cGAS activation, ER stress, and metastasis.

Main Results:

• CIN-induced cGAS-STING activation leads to signal re-wiring in cancer cells, promoting a pro-metastatic tumor microenvironment.
• This re-wiring involves type I interferon tachyphylaxis downstream of STING and increased ER stress.
• Reversing CIN, inhibiting STING, or blocking ER stress abrogates CIN-dependent pro-metastatic effects and suppresses metastasis in immune-competent settings.
• STING inhibitors effectively reduce CIN-driven metastasis in various cancer types, dependent on tumor cell-intrinsic STING.
• CIN and cGAS activation in human TNBC correlate with ER stress, immune suppression, and metastasis.

Conclusions:

• The cGAS-STING pathway and subsequent ER stress are critical mediators of CIN-driven metastasis.
• Targeting tumor cell-intrinsic STING offers a promising therapeutic strategy for CIN-driven cancers.
• CIN-induced inflammation and associated ER stress are key factors in metastasis and immune suppression, particularly in TNBC.