Therapeutic response and regulation of metastasis differ by organ site


Three researchers discussed how the microenvironments of different organ sites regulate metastasis and therapeutic response during the Annual Meeting symposium Organ Specific Regulation of Metastasis. The session was presented on Monday, April 17, and can be viewed on the virtual meeting platform by registered Annual Meeting participants through July 19, 2023.

Mikala Egeblad, PhD
Mikala Egeblad, PhD

Different organs have distinct microenvironments, explained symposium chair Mikala Egeblad, PhD, Professor and Cancer Center Program Co-Leader at Cold Spring Harbor Laboratory. “The microenvironments in these different organs are not static,” she said. “There are complex interactions between systemic host responses and the local microenvironments.”

Egeblad presented research examining how chronic stress can promote metastasis through local changes to the lung microenvironment.

She used mouse models to demonstrate that stress drives pro-metastatic changes to the lung microenvironment, such as increased accumulation of extracellular matrix components, fewer CD8+ T cells, and more neutrophils. Increased infiltration of neutrophils, resulting in a greater neutrophil-to-lymphocyte ratio, has been previously linked to stress.

Egeblad and colleagues also found that stress-induced metastasis was dependent on neutrophils, potentially due to gene expression changes that occur in neutrophils under stressful conditions and via the formation of neutrophil extracellular traps (NETs).

“We believe that these changes in neutrophils and NETs are causing ECM accumulation in the lung, T-cell inhibition, and release of other pro-inflammatory factors,” she said, suggesting that these effects may increase the susceptibility of the lung to colonization by metastatic cancer cells. Egeblad proposed targeting neutrophils and/or NETs as a potential therapeutic approach but acknowledged that this approach needs to be evaluated in clinical studies.

Neta Erez, PhD
Neta Erez, PhD

Neta Erez, PhD, described how systemic instigation of neuroinflammation facilitates brain metastases.

“We know that changes in the metastatic niche precede metastasis formation, but the early events in patients are a black box,” said Erez, Professor of Pathology and Vice Dean of the Faculty of Medicine at Tel Aviv University, Israel.

Brain metastases are two to 10 times more frequent than primary brain tumors and are associated with a median survival of less than one year, Erez explained.

Neuroinflammation is a hallmark of brain metastasis and is characterized by activation of astrocytes and microglia and by increased permeability of the blood-brain barrier; these enable the release of pro-inflammatory molecules and the infiltration of leukocytes, respectively.

In a mouse model of melanoma, Erez and colleagues found that neuroinflammation preceded brain metastasis. In addition, astrocytes from brains that harbored metastases had increased expression of the proinflammatory marker CXCL10 compared with astrocytes from brains without metastases. Brain-tropic melanoma cells were enriched for the CXCL10 receptor CXCR3, and depleting CXCR3 in melanoma cells reduced the occurrence of brain metastasis.

“[The CXCL10–CXCR3 axis] is hijacked by melanoma cells to facilitate brain-tropism and metastatic colonization in the brain,” she said.

Further experiments revealed that high levels of systemic lipocalin-2 (LCN2) were associated with brain metastases and poor survival in patients with melanoma. Furthermore, they found that astrocytes expressed the LCN2 receptor, SLC22A7, and that LCN2 was sufficient and necessary to induce inflammatory activation of astrocytes.

“LCN2 is a potential prognostic marker and may be a novel therapeutic target for the prevention or treatment of brain metastasis,” Erez concluded.

Erik Sahai, PhD
Erik Sahai, PhD

Erik Sahai, PhD, reviewed the mechanisms of organ-specific resistance to targeted therapies and immunotherapies.

There is a common metastatic cascade, beginning with local invasion and intravasation, survival in circulation, arrest in distant organ, extravasation, micrometastasis, and macrometastatic growth, Sahai explained. But how that cascade produces metastases depends in large part on the tumor microenvironment (TME) of the target organ.

In bone, the TME is characterized by osteoblasts and osteoclasts. In the liver, it’s characterized by hepatocytes, stellate cells, and Kupffer cells. In the brain, it’s marked by astrocytes, neurons, and microglia. In the lungs, it’s marked by alveolar type I and type II cells.

The TME can undermine targeted therapy, with signaling in the TME of certain organs allowing cancer cells to circumvent the effects of therapeutic inhibitors, explained Sahai, Principal Group Leader and Assistant Research Director at the Francis Crick Institute, London. In the brain, for example, cerebrospinal fluid protects metastatic melanoma cells from BRAF inhibitors.

As a result, metastases in different organs may respond differently to the same therapy, as demonstrated in results reported by Sahai. In mice, subcutaneous melanoma lesions responded well to anti-PD-1 therapy, but liver metastases were resistant.

Therefore, Sahai noted, the site of the metastasis, not just the cancer genotype, must be a consideration when treating metastases.

Claim Your CME/MOC Credits for the Annual Meeting

Access to the AACR Annual Meeting 2024 virtual meeting platform and all on-demand sessions is available through July 10, 2024. Attendees can claim AMA PRA Category 1 Credit(s)™ or Medical Knowledge MOC points, based on participation. For more information and to see a list of designated sessions, visit the AACR Continuing Medical Education page.

Claim Your CME/MOC Credits for the Annual Meeting

Access to the AACR Annual Meeting 2024 virtual meeting platform and all on-demand sessions is available through July 10, 2024. Attendees can claim AMA PRA Category 1 Credit(s)™ or Medical Knowledge MOC points, based on participation. For more information and to see a list of designated sessions, visit the AACR Continuing Medical Education page.