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Loss of HAPLN1 protein in aging skin raises metastasis risk

Age-related changes in skin structure, and in the lymphatic system, appear to create conditions that make skin cancer metastasis easier, according to two studies from researchers at The Wistar Institute in Philadelphia.

Both papers were published online ahead of print in Cancer Discovery (Oct. 2, 2018, here and here).

In these new studies, the Weeraratna Lab—led by Ashani Weeraratna, PhD—characterized architectural changes that occur in the extracellular matrix (ECM) in the skin and surrounding the lymphatic vessels. The changes they looked at promote the spread of melanoma cells to distant sites by influencing tumour cell and immune cell trafficking.

Dr. Weeraratna is the Ira Brind Professor and professor and co-leader of the Immunology, Microenvironment and Metastasis Program at Wistar.

Dr. Weeraratna and her collaborators also discovered a fundamental role played by the HAPLN1 protein—part of the ECM—in the molecular mechanisms underlying these changes. In one of the studies they observed “dramatic” changes in the expression of many ECM proteins produced by fibroblasts, including HAPLN1.

“The same structural changes that happen in our skin with aging and cause the appearance of wrinkles are also responsible for the increased risk of metastasis in older melanoma patients,” said Dr. Weeraratna, senior author in both studies, in a press release.

“With advancing age, the network of fibres that supports our skin loses the ‘basket weave’ organization that is characteristic of younger skin, and becomes looser. In a tumour setting, we think of it as a barrier that helps contain the tumour cells by inhibiting their motility while favouring infiltration of immune cells into the tumour mass. In older patients, due to the loss of HAPLN1, this barrier becomes less efficient. These age-related changes also affect the way immune cells enter the tumour, which may have important implications for immunotherapy.”

In that first study, Dr. Weeraratna and colleagues showed through manipulating expression levels of HAPLN1 in three-dimensional human skin reconstruct models and in mouse skin models, that loss of the protein creates a permissive microenvironment that favours escape of tumour cells while hampering trafficking of antitumor immune cells, particularly CD8+ T cells.

As well, injecting recombinant HAPLN1 around the tumour in melanoma mouse models reduced the size and metastatic capability of the tumour.

The second study showed that age-associated loss of integrity in lymphatic vessels allows melanoma cells to escape the lymphatic system and the proximal lymph nodes more easily, so that they can reach more distant sites. This was also found to be associated with loss of HAPLN1.

“It is known that older individuals with melanoma have a lower incidence of lymphatic metastasis than younger patients, yet higher rates of distant visceral metastasis,” said Dr. Weeraratna. “Our observation that older lymphatic vessels and lymph nodes are less efficient as a barrier to contain the metastatic cells may underlie that observation.”

When the team injected recombinant HAPLN1 into the draining lymph nodes of aged melanoma-bearing mice, it increased the rates of lymphatic micrometastases while reducing the frequency of lung metastasis. The authors say this suggests that containment of the metastatic cells in the local lymphatic system may have therapeutic implications when coupled to surgical resection of the sentinel lymph nodes.

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